New ACR Rheumatoid Arthritis Guideline: Emphasis on Methotrexate

The American College of Rheumatology (ACR) has issued new guidelines on the treatment of rheumatoid arthritis, addressing questions about initial treatment with methotrexate and minimizing reliance on glucocorticoids. Use of these medications in specific high-risk populations also was included.

One major focus of the guideline was the emphasis on maximizing the use of methotrexate as the main disease-modifying antirheumatic drug [DMARD] before adding another medication, said lead author Liana Fraenkel, MD, of Yale University School of Medicine in New Haven, Connecticut and Berkshire Medical Center in Pittsfield, Massachusetts.

“Seventy percent of patients can stay on one medication and not escalate if methotrexate is used diligently, but that takes some effort. It requires thinking about how to deal with side effects and escalating the dose,” she told MedPage Today.

“We know that a lot of patients, especially in the U.S., are on biologics — more than we would expect if methotrexate was used to its full advantage. It’s safer to stay on just one medication, and methotrexate has been proven to have efficacy over the long term,” Fraenkel added.

The guideline states that methotrexate is “strongly recommended” over hydroxychloroquine or sulfasalazine as monotherapy for DMARD-naive patients who have moderate-to-high disease activity, and is also preferred initially over a biologic or targeted synthetic medication. Initial methotrexate monotherapy also was “conditionally recommended” over triple therapy (with sulfasalazine plus hydroxychloroquine) and was preferred over use in combination with a tumor necrosis factor (TNF) inhibitor or other type of biologic or targeted synthetic DMARD.

Strong recommendations were those “for which the panel is highly confident that the recommended option favorably balances the expected benefits and risks for the majority of patients in clinical practice,” while for conditional recommendations, the panel was “less confident that the potential benefits outweigh the risks.”

The use of the oral methotrexate formulation was favored as initial treatment, with titration over 4 to 6 weeks to a weekly dose of at least 15 mg. For patients who have difficulty tolerating this approach, the oral dose can be split or subcutaneous administration can be tried, the guideline advised.

For patients who do not reach the target of low disease activity or remission with maximal doses of methotrexate, the addition of a biologic agent or targeted synthetic DMARD was conditionally recommended in preference to triple therapy, although triple therapy may be more suitable in certain circumstances such as lower resource settings and in patients with comorbidities that could be more safely managed with these conventional DMARDs.

The panel did not provide a recommendation for the choice between biologics and targeted synthetic DMARDs when treatment adjustment is needed for patients with an inadequate response to methotrexate. The panel did note, however, that a drug safety communication issued on Feb. 4, 2021, advised the public “that preliminary results from a safety clinical trial show an increased risk of serious heart-related problems and cancer with the arthritis and ulcerative colitis medicine” tofacitinib (Xeljanz) compared with TNF inhibitors.

“But to the best of my knowledge there hasn’t been a peer-reviewed final report and no further recommendation by the FDA, so until that happens the ACR’s standard procedure is to provide updates in real time if anything significant happens,” Fraenkel said.

A second focus of the guideline was minimizing any use of glucocorticoids. The panel agreed that avoidance of glucocorticoids is desirable because of the potential toxicity of these agents, while acknowledging that “short-term glucocorticoids are frequently necessary to alleviate symptoms prior to the onset of action of DMARDs.” But glucocorticoids should be used at “the lowest effective dose for the shortest duration possible,” the document emphasized.

With regard to the question as to whether DMARDs can be tapered or discontinued, the guideline advises that patients who are in low disease activity or remission for at least 6 months can attempt reducing the dose or extending the interval between doses, but therapeutic doses of at least one DMARD should continue because of the risks for flare and long-term damage when all DMARDs are withdrawn.

The guideline also offered recommendations for certain specific subgroups of patients. For instance, for patients with subcutaneous nodules, methotrexate was conditionally recommended, but if the nodules worsen, an alternative DMARD should be tried. Methotrexate also was conditionally recommended for the treatment of patients with inflammatory arthritis with mild, stable airway or parenchymal lung disease, despite the observation that pre-existing pulmonary disease is a risk factor for methotrexate-associated pneumonitis.

“However, the overall risk of worsening lung disease attributable to methotrexate is uncertain, and alternative DMARDs have also been associated with lung disease,” Fraenkel and colleagues wrote.

For patients with heart failure, the use of a non-TNF biologic or targeted synthetic DMARD was conditionally recommended over TNF inhibitors for patients who don’t respond adequately to a conventional DMARD, because worsening heart failure has been observed with the use of TNF inhibitors.

Patients who develop hypogammaglobulinemia but have no infections can continue on treatment with rituximab (Rituxan), because of the “uncertain clinical significance” of this laboratory finding, the guideline noted.

The panel concluded that additional data “may modify the direction and/or strength of specific recommendations” as new published information becomes available.